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Characterizing heterochromatin dysfunction as a driving alteration in cancer

将异染色质功能障碍描述为癌症的驱动改变

基本信息

批准号：
9796959
负责人：
Jason Huse
金额：
$ 36.6万
依托单位：
UNIVERSITY OF TX MD ANDERSON CAN CTR
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-07-01 至 2024-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9796959
关键词：
ATRX gene Address Automobile Driving Behavior Binding Proteins Biological Biological Process Biology Brain Neoplasms Cancer Biology Cancerous Cell Line Cells Chromatin Collaborations Complex Confocal Microscopy Coupled Custom DNA DNA Damage Data Development Developmental Gene Elements Epigenetic Process Event Evolution Expression Profiling Functional disorder G-Quartets Gene Expression Gene Expression Regulation Gene Silencing Genes Genetic Transcription Genomic Instability Glioma Gliomagenesis Heterochromatin Histone Deacetylase Histones Human In Vitro Isocitrate Dehydrogenase Link Malignant - descriptor Malignant Glioma Malignant Neoplasms Malignant neoplasm of brain Mediating Mental Retardation Microscopic Microscopy Modeling Molecular Mouse Cell Line Mus Mutation Normal Cell Normal tissue morphology Nuclear Lamina Nucleosomes Oncogenic Pathogenesis Pathway interactions Patients Pharmaceutical Preparations Phenotype Play Positioning Attribute Primary Brain Neoplasms Process Proteins Publishing Reagent Recurrence Regulation Regulator Genes Research Role Signal Pathway Site Stem cells Stretching Structure System Thalassemia Therapeutic Variant Work alpha-Thalassemia base body system cell motility chromatin protein combat design epigenetic profiling epigenomics genetic approach genome-wide glioma cell line in vivo insight mutant nervous system development novel programs replication stress resistance mechanism therapeutic target treatment strategy tumor tumorigenesis

项目摘要

PROJECT SUMMARY Recent research has emphatically confirmed that cancer is characterized not only by mutations in genes, but also by disturbances in gene regulation. This latter mechanism often involves chromatin—the proteins and regulatory molecules directly associated with DNA—and their influence on gene expression through so-called “epigenetic” effects. Inactivation of the chromatin regulator protein ATRX (-thalassemia mental retardation X- linked) is commonly seen in several cancer variants, including malignant glioma, the most common and deadly primary brain cancer. While ATRX has been implicated in a variety of biological processes in normal cells, its role in cancer biology is less clear. In our recent work, we confirmed that ATRX deficiency dramatically alters chromatin and underlying gene expression, while also rendering DNA more susceptible to damage, breakage, and other abnormalities. In particular, we found that ATRX loss disrupts the organization of specific regions of chromatin, called heterochromatin, where key developmental genes undergo systematic silencing as organ systems mature. Prior work by other groups suggests that heterochromatin dysfunction, and loss of underlying gene silencing, contributes to cancer development. The central hypothesis of our proposal is that disruptions in heterochromatin promote glioma formation by altering gene expression and inducing damage and abnormalities in DNA. In this project, we will address our central hypothesis using customized human and mouse cell lines that recapitulate the core biological and molecular features of ATRX-deficient glioma, along with bona fide glioma cell lines, with and without ATRX deficiency, derived directly from patients. Some of our studies will incorporate glioma models in mice. Furnished with these reagents, we will conduct epigenetic profiling, coupled with microscopy and molecular and cell biological approaches, to correlate chromatin-related findings with cancerous behaviors. In our first aim, we will characterize the mechanisms by which ATRX deficiency alters heterochromatin in glioma. In our second aim, we will delineate the extent to which heterochromatin dysfunction in ATRX-deficient glioma promotes damage and abnormalities in DNA. Finally, in our third aim, we will identify key gene expression changes associated with ATRX deficiency that drive cancerous behavior in glioma and investigate mechanisms by which they can be therapeutically targeted. If successful, our work will characterize an entirely novel molecular process driving cancer formation and provide insights into treatment strategies for deadly brain tumors.

项目摘要最近的研究已经明确证实，癌症的特征不仅在于基因突变，也是由于基因调控的紊乱。后一种机制通常涉及染色质-蛋白质和直接与DNA相关的调节分子，以及它们通过所谓的 “表观遗传”效应。染色质调节蛋白ATRX（β-地中海贫血智力低下X- 连锁）常见于几种癌症变体，包括恶性神经胶质瘤，最常见和致命的原发性脑癌虽然ATRX已涉及正常细胞中的多种生物过程，但其在癌症生物学中的作用不太清楚。在我们最近的工作中，我们证实ATRX缺乏会显着改变染色质和潜在的基因表达，同时也使DNA更容易受到损害，断裂，和其他异常。特别是，我们发现ATRX损失破坏了特定区域的组织，异染色质，其中关键的发育基因经历系统性沉默，系统成熟。其他研究小组先前的工作表明，异染色质功能障碍，以及潜在的基因沉默，有助于癌症的发展。我们建议的核心假设是，异染色质通过改变基因表达和诱导损伤促进胶质瘤形成， DNA的异常在这个项目中，我们将解决我们的中心假设使用定制的人类和小鼠细胞系概括了ATRX缺陷胶质瘤的核心生物学和分子特征，沿着用真正的神经胶质瘤细胞系，有或没有ATRX缺陷，直接来自患者。我们的一些研究将包括小鼠神经胶质瘤模型。有了这些试剂，我们将进行表观遗传分析，再加上显微镜和分子和细胞生物学方法，以关联染色质相关癌症行为的发现。在我们的第一个目标中，我们将描述ATRX 缺陷改变了胶质瘤中的异染色质。在我们的第二个目标中，我们将描述 ATRX缺陷胶质瘤中异染色质功能障碍促进DNA损伤和异常。最后在我们的第三个目标是，我们将确定与ATRX缺乏相关的关键基因表达变化，神经胶质瘤中的癌行为，并研究它们可以被治疗靶向的机制。如果如果成功，我们的工作将描述一个全新的驱动癌症形成的分子过程，对致命脑肿瘤治疗策略的见解。